© 1995 American Heart Association, Inc.
Articles |
Acetylcholine Elicits a Rebound Stimulation of Ca2+ Current Mediated by Pertussis Toxin–Sensitive G Protein and cAMP-Dependent Protein Kinase A in Atrial Myocytes
From the Department of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois.
Correspondence to Stephen L. Lipsius, PhD, Department of Physiology, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153.
Abstract Cholinergic inhibition of atrial contraction is
typically followed by a rebound positive inotropic response. In the
present study, we used a nystatin–perforated patch whole-cell
recording method to determine whether acetylcholine (ACh) elicits a
rebound stimulation of L-type Ca2+ current
(ICa,L) in cat atrial myocytes. ACh (1 µmol/L) decreased
basal ICa,L (-19±2%). Within 
30 s of returning to
ACh-free solution, basal ICa,L exhibited a rebound increase
above the control level (+61±7%) that returned to the control level
within 4 to 5 minutes. ACh elicited concomitant changes in cell
shortening, ie, a decrease followed by a rebound increase. The
EC50 and maximal response of ACh-induced inhibition and
rebound stimulation of ICa,L were 1.9x10-9
mol/L and -30%, respectively, and 2.9x10-8 mol/L and
+64%, respectively. All effects of ACh on ICa,L were
blocked by prior exposure to 1 µmol/L atropine or 100 µmol/L
AFDX116 and unaffected by 0.2 µmol/L pirenzepine or 1 µmol/L
propranolol. In the presence of ACh, exposure to atropine elicited
stimulation of ICa,L. ACh-induced inhibition and rebound
stimulation of current were independent of external
Ca2+. Rebound stimulation of ICa,L was
associated with a negative shift in the voltage dependence of
ICa,L activation. Inhibition of protein kinase A by 50
µmol/L Rp-cAMPs decreased basal ICa,L by 36±1% and
abolished the rebound stimulation of ICa,L. Forskolin (0.01
µmol/L) or isoproterenol (0.01 µmol/L) had no effect on basal
ICa,L, but each accentuated the rebound
increase in ICa,L. When adenylate cyclase was maximally
stimulated with 1 µmol/L isoproterenol plus 2 µmol/L forskolin, ACh
decreased ICa,L but failed to elicit rebound stimulation of
ICa,L. Milrinone (10 µmol/L) increased basal
ICa,L by 70±7% and significantly attenuated the rebound
stimulation of ICa,L. Exposure to 1 mmol/L 8-bromo-cGMP
elicited a small decrease in basal ICa,L, attenuated
ACh-induced inhibition, and enhanced the rebound stimulation of
ICa,L. Incubation in pertussis toxin prevented all
ACh-induced changes in ICa,L. Inhibition of nitric oxide
synthase by 100 µmol/L
NG-monomethyl-L-arginine
(L-NMMA) decreased basal ICa,L by -20±5%, prevented
ACh-induced inhibition, and markedly attenuated the rebound stimulation
of ICa,L. We conclude that in cat atrial myocytes ACh acts
via M2 muscarinic receptors and pertussis toxin–sensitive
G protein to inhibit basal ICa,L and that on withdrawal ACh
elicits a rebound stimulation of ICa,L. Rebound stimulation
of ICa,L is mediated via cAMP-dependent protein kinase A
enhanced by ACh-induced inhibition of phosphodiesterase. This mechanism
contributes directly to the positive inotropic response that follows
cholinergic inhibition of atrial contraction.
Key Words: perforated patch • whole-cell patch • isoproterenol • pertussis toxin • phosphodiesterase
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